Project Summary Fragile X Syndrome (FXS) is the most common inherited monogenic cause of autism spectrum disorder (ASD) or intellectual disability (ID). In human, FXS is caused by silencing of the FMR1 gene, which leads to a loss of the Fragile X Mental Retardation Protein (FMRP). FXS patients exhibit severe deficits in attention and executive functioning, as well as alterations in neural activity in the prefrontal cortex (PFC), which subserves these functions. FXS patients also have abnormal prefrontal morphology that associates with impairments in behaviors supported by PFC functioning. To date, all pharmacological intervention strategies that have been successful in reversing FXS-relevant phenotypes in mice have not proven to be effective in human clinical trials. Rats offer several advantages over mice for probing mechanistic impairments associated with FXS. Rats exhibit much more complex behaviors than mice, readily learn PFC-dependent tasks, have larger brains which facilitate in vivo electrophysiology and imaging, and have PFC anatomical connectivity and functional homology that has been studied extensively. Thus, we will use the Fmr1-deficient rat model of FXS in this study, which will expand our understanding of the role of FMRP in PFC function and provide a superior platform for treatment development targeting PFC function in FXS. Furthermore, this project will use both male and female Fmr1 knockout (KO) rats in order to elucidate potential sex differences, as well as heterozygous females in order to study the dose-dependent effect of Fmrp. Our preliminary data show that Fmr1-deficient rats have impaired sustained attention, which parallels the attentional phenotype observed in humans. We hypothesize that aberrant oscillatory activity in prefrontal neural circuits is an important neurobiological consequence of Fmrp loss that follows from disrupted morphology in this region and underlies behavioral deficits in attention. In this proposal, we will address the anatomical and functional mechanisms by which loss of Fmrp affects attention in Fmr1-deficient rats. Because the PFC likely also underlies cognitive dysfunction in FXS patients, by elucidating the physiological and morphological abnormalities in the Fmrp-deficient rat PFC, these studies will lay the groundwork for identifying a new target region for treatment. Moreover, as much of the phenotype and many of the neural abnormalities associated with FXS are shared in a subset of individuals with idiopathic ASD and ID, clarifying the neural correlates of attention dysfunction in FXS may also deepen our understanding of ASD and ID and lead to new treatment opportunities for ASD and ID broadly.